The human sis proto-oncogene contains the coding sequence for one of two polypeptide chains present in preparations of biologically active human platelet-derived growth factor (PDGF). We sought to determine whether this normal coding sequence could ba activated as a transforming gene by appropriate in vitro manipulations. A human clone, c-sis clone 8, which contains all of the v-sis-related sequences present in human DNA, was shown to be transcriptionally inactive when transfected into NIH/3T3 cells. When placed under the control of a retrovirus LTR, the clone was transcribed at levels comparable to that observed in cells transformed by SSV DNA. In spite of its transcriptional activation, c-sis clone 8 DNA did not express detectable sis/PDGF-2 proteins and lacked biologic activity. A putative upstream exon was identified by its ability to detect the 4.2-kb sis-related transcript in certain human cells. When this putative exon was inserted in the proper orientation between the LTR and c-sis clone 8, the chimeric molecule acquired high titered transforming activity, comparable to that of SSV DNA. Moreover, transformants containing this construct were shown to express human sis/PDGF-2 translational products. These findings establish that the normal coding sequence for a human growth factor has transforming activity when expressed in an appropriate assay cell.